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Proof-of-Concept Phase II Study to Evaluate the Anti-Tumor Activity of Sorafenib Along With Pathological and Molecular Changes in Tumor Samples From Patients With Resectable Hepatocellular Carcinoma

Phase 2
18 Years
Open (Enrolling)
Liver Cancer

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Trial Information

Proof-of-Concept Phase II Study to Evaluate the Anti-Tumor Activity of Sorafenib Along With Pathological and Molecular Changes in Tumor Samples From Patients With Resectable Hepatocellular Carcinoma



- To assess anti-tumor activity of neoadjuvant sorafenib tosylate in tumor samples from
patients with resectable hepatocellular carcinoma (HCC).


- To characterize pathologic findings in sorafenib tosylate pre-treated patients
undergoing surgical resection for HCC: 1-2 core tumor biopsies will be performed prior
to treatment and at day 35.

- To evaluate the number of R0 resections in these patients.

- To correlate pathological biomarker changes in resected tumors after 4-week treatment
with sorafenib tosylate in comparison with biopsies obtained prior to treatment in
these patients.

- To evaluate plasma biomarkers, including PIGF, VEGF-A, VEGF-C, sVEGFR2, sVEGFR3, sKIT,
IL-6, Ang2, IL-8, bFGF, AFP, collagen 4, endostatin, thrombospondin, TSP-1 and
angiostatin, and CXCL12 at baseline, day 28, and the day before surgery.

- To identify potential biomarkers of sensitivity and/or resistance on biological and
pathological samples of these patients (exploratory).

- To characterize the safety profile of sorafenib tosylate in these patients.

- To assess the tolerance of liver resection after sorafenib tosylate treatment of these

OUTLINE: This is a multicenter study.

Patients receive oral sorafenib tosylate twice daily on days 1-28 in the absence of
unacceptable toxicity. Approximately 7 days after completion of sorafenib tosylate therapy,
patients undergo liver resection.

Blood and tissue specimens are collected periodically for laboratory and biomarker
assessments. Biomarkers include both molecular markers investigating the direct antitumor
effects of sorafenib tosylate against cancer cells vs the effects of the drug on

After completion of study treatment, patients are followed up on day 50 and at 3 months
after surgery.

Inclusion Criteria


- Histologically confirmed hepatocellular carcinoma (HCC)

- Fibrolamellar or mixed histology allowed

- No cholangiocarcinoma or other tubal disease

- Must be eligible for conservative hepatic resection or liver resection with curative

- No cirrhosis with Child-Pugh score > 7

- Chronic liver disease without liver insufficiency and without portal liver
hypertension allowed

- No known history or presence of metastatic brain or meningeal tumors


- ECOG performance status 0-1

- Life expectancy ≥ 3 months

- WBC > 3,000/µL

- ANC > 1,500/µL

- Platelet count ≥ 100,000/µL

- Hemoglobin ≥ 9 g/dL

- Bilirubin < 1.5 times upper normal limit (ULN)

- AST and ALT ≤ 5 times UNL

- Alkaline phosphatase ≤ 5 times ULN

- Serum creatinine < 2 times ULN

- PT/INR/PTT < 1.5 times UNL

- Amylase and lipase < 1.5 times ULN

- Negative pregnancy test

- Fertile patients must use effective contraception

- Body mass index 18.5-30 kg/m^2 (WHO normal range: 18.5-25 kg/m^2)

- Able to swallow oral compound

- No criterion for unresectability or medical condition that contraindicates surgical

- No serious concurrent systemic disorder incompatible with the study, including any of
the following:

- Uncontrolled hypertension (i.e., BP > 150/100 mm Hg despite optimal therapy)

- Active uncontrolled infection

- Active alcoholism

- No prior medical disorder, including any of the following:

- Cardiac arrhythmias requiring anti-arrhythmics (excluding beta-blockers or
digoxin for chronic atrial fibrillation)

- Active coronary artery disease or ischemia

- Myocardial infarction within the past 6 months

- NYHA class III-IV congestive heart failure

- Pulmonary embolism within the past 6 months

- Gastrointestinal bleeding within the past 6 months

- No other prior malignancy within the past 5 years, except basal cell or squamous cell
skin carcinoma or cured in situ cervical carcinoma

- No history or concurrent seizure disorder requiring medications (e.g., antiepileptic

- No history of HIV infection, or chronic hepatitis B or C

- No active clinically serious bacterial or fungal infection (i.e., grade 2 CTCAE v. 3)

- No condition that is unstable or could jeopardize the safety of the patient and
his/her compliance with the study

- No substance abuse or medical, psychological, or social condition that could
interfere with adherence to the study

- No known or suspected allergy to the investigational agent or to any agent given

- No presence of asthenia or rash > CTC grade 1 at enrollment

- Must be registered in a national health-care system


- No prior orthotopic liver transplantation

- Not a candidate for orthotopic liver transplantation

- No prior systemic or loco-regional treatment for HCC

- No prior organ allograft

- No treatment with any other investigational medicinal product within the past 28 days

- No concurrent treatment with full-dose anticoagulants

- Deep-vein or catheter-associated thrombosis prophylaxis allowed

- Warfarin or heparin therapy allowed if the coagulation parameters were within
the acceptable ranges prior to initiation of anticoagulant therapy

- No concurrent or chronic co-administration of CYP3A4 inducers (e.g., rifampin,
Hypericum perforatum, phenytoin, carbamazepine, phenobarbital, or dexamethasone)

Type of Study:


Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Antiangiogenic effects of sorafenib tosylate

Safety Issue:


Principal Investigator

Sandrine Faivre

Investigator Role:

Principal Investigator

Investigator Affiliation:

Hopital Beaujon



Study ID:




Start Date:

May 2010

Completion Date:

Related Keywords:

  • Liver Cancer
  • adult primary hepatocellular carcinoma
  • localized resectable adult primary liver cancer
  • Liver Neoplasms
  • Carcinoma, Hepatocellular